Microgranules based on active principle and method for making same

ABSTRACT

The invention concerns a microgranule consisting of a core coated with at least a coating layer, said coated core comprising at least an active principle. The invention is characterised in that the core and said coating layer contain each between 80 and 95 wt. % of active principle, the complement to 100% consisting of at least a binding agent, and the coated core has a substantially spherical shape. The invention also concerns the method for making such microgranules.

This application claims priority to PCT Application No. PCT/FR01/03584filed on Nov. 15, 2001, which was published as WO 02/39981 on May 23,2002. The application also claims priority to French Application No.00.14803 filed on Nov. 16, 2000.

TECHNICAL FIELD OF THE INVENTION

The invention relates to a microgranule consisting of a coated corecomprising at least one active principle. It also relates to method formaking said microgranule and to the pharmaceutical compositionscontaining a plurality of said microgranule.

BACKGROUND

The document WO 95/22319 describes a method for making byextrusion/spheronization fine particles based on an active principle.The fine particles obtained have a size of between 50 μm and 1 mm. Inparticular, the examples describe particles having a size equal to 300μm, comprising up to 72% of active principle in the presence of at leastthree excipients including in particular an extrusion agent. Inaddition, these same examples and in particular formula 1 c shows thatthis method does not make it possible to obtain fine particles of thisorder of size with a high concentration of active principle, equal to95%. Finally, the fine particles obtained at the end of the method havea surface which is too irregular to allow subsequent satisfactorytreatment, the coating designed to mask the taste of the activeprinciple requiring, for example, a high level of coating.

The document EP-A-443572 describes a coating composition which can beapplied in various forms and in particular microgranules designated hereby the expression “fine granules”. It is indicated that at least 75% ofthe population of microgranules have a size of between 1 and 500 μm. Noinformation is given relating to the concentration of active principlein the microgranule.

The document FR-A-2 419 722 describes microgranules of active principleand in particular of ferritin and their method of preparation. Thesemicrogranules consist of a core comprising a first coating obtained byspraying an aqueous suspension of active principle, the cohesion of saidfirst coating with the core being brought about by uniform dispersion,between each spraying step, of small quantities of talc (see inparticular page 7, example 3). The core thus coated has, in addition, asecond coating, whose nature depends on the characteristics of releaseof the desired active principle. In practice, the core itself can havetwo different forms. Thus, in a first embodiment, the core consistsexclusively of inert material, for example of the sucrose type. In asecond embodiment, (example 3), the core exists in the form of a granulebased on a binder (for example starch) and an active principle in ratiosof 50/50.

The method of manufacture and the microgranule thus obtained exhibit anumber of disadvantages. As regards first of all the method ofmanufacture, it requires at least four steps, which are the manufactureof the core, and then, alternatively, the application of the firstcoating, and of the talc dispersion and finally the application of thesecond coating. Such a method is particularly long and cannot beperformed continuously. In addition, the cohesion of the first coatingonto the core is not always homogenous, leading to coated cores havingan irregular surface and thereby increasing the quantity of materialnecessary for the second coating. As regards the microgranule as such,it is indicated that the core before coating has a size of between 0.3and 0.5 millimeters (see examples) for a concentration of activeprinciple representing only 50% of the mass of the core.

Accordingly, the first problem which the invention proposes to solve isto provide microgranules whose core, before coating of the functionallayer(s) conferring on the microgranule the desired characteristics ofrelease of the active principle and/or of masking the taste, is asconcentrated as possible in active principle.

The second problem which the invention proposes to solve is to provide amicrogranule whose nucleus, before coating the functional layer(s), isappreciably spherical so as to reduce its specific surface and thusreduce the quantity of material necessary for subsequent coating.

The third problem which the invention proposes to solve is to provide amicrogranule whose nucleus, before coating the functional layer(s), hasa size which is as small as possible, advantageously a median size ofless than 500 μm.

SUMMARY OF THE INVENTION

The subject of the invention is therefore a microgranule consisting of acore coated with at least one coating layer, said coated core comprisingat least one active principle.

This microgranule is characterized in that the core and said coatinglayer each contain between 80 and 95% by weight of active principle, thebalance for 100% consisting of at least one binder, and in that thecoated core has a substantially spherical shape.

Below an active principle concentration of 80%, the microgranule titeris not sufficient and the proportion of binder is too high, leading tothe size of the microgranule being increased. For a concentrationgreater than 95%, the cohesion between the particles of active principleis not satisfactory because of the extremely low proportion of binder.

In a preferred embodiment, the core and the coating layer each containbetween about 85 and 93%, advantageously 90% by weight of activeprinciple.

In an advantageous embodiment, the balance for 100% by weight of thecore and of the coating layer consists exclusively of a binder.

The choice of “binder” will be determined as a function not only of itscapacity to bind the particles of active principle to each other in thecoated core, but also of the desired functional characteristics of thecoated core, whether in the presence or in the absence of subsequentfunctional coating. The expression “functional characteristics” denotesin particular, but without limitation, the properties of masking oftaste and/or of release (modified or otherwise) of the active principle.

These functional characteristics depend on: 1) the physicochemicalcharacteristics of the binder used (solubility, permeability, glasstransition temperature, and the like); and 2) on the nature of theactive principle (solubility, bitterness, and the like).

In other words, before any subsequent functional coating, themicrogranule of the invention already has specific characteristics thusmaking it possible to reduce the thickness of the subsequent coating andtherefore the size of the final microgranule.

In practice, the binder is chosen from the group comprising ethylcellulose, hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC),hydroxypropyl methyl cellulose (HPMC), acrylic polymers, methacrylicpolymers, amonio-methacrylate copolymer, polyacrylate, methacrylic acidcopolymer and polyvinylpyrrolidone.

According to another characteristic, the binder contained in the coatinglayer and that contained in the core may be identical or different.

DETAILED DESCRIPTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatmay be embodied in a wide variety of specific context. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

As already stated, another objective of the invention is to reduce thesize of the coated microgranule before coating the optional subsequentfunctional layer. The high titer of the microgranules of the inventionmakes it possible to partially fulfill this objective. To further reducethe size of the microgranules, the size of the particles of activeprinciple varies between 10 and 30 μm.

In practice, the size of the coated microgranules of the inventionbefore optional subsequent coating is less than 500 μm, advantageouslybetween 200 and 300 μm.

Of course and as already stated, the coated core constituting themicrogranule of the invention may comprise an additional functionalcoating, in general of polymeric origin, whose nature will depend on thedesired characteristics of the final formulation and in particular ofmasking taste and/or of modified or unmodified release of activeprinciple.

Because of the specific method of production which will be describedlater, the microgranules of the invention have, in addition, theadvantage of being substantially spherical, thus having a reducedspecific surface area which makes it possible to coat a subsequent layerof raw material in reduced quantities compared with the knownmicrogranules of the prior art. This subsequent layer preferablycomprises a polymer whose application to the microgranules will make itpossible to obtain the desired final characteristics.

Moreover, the microgranules of the invention may be used in variousgalenical forms such as in particular sachets, gelatin capsules, liquidsuspensions, suspensions intended for reconstitution immediately beforeuse. They can also enter into the composition of tablets which areorodispersible or not. In this regard, the reduced size of themicrogranules of the invention makes it possible to reduce theproportion of compression excipients (for example the diluents)necessary for producing a homogeneous mixture before compression, whichmakes it possible to have a final form of smaller size and weightcompared with known tablets of the same size and to also reduce thecompression forces.

In this regard, the invention relates more particularly to fastdisintegrating multiparticulate type tablets such as those described bythe applicant in the document FR-A-2 679 451, and fast dispersible typetablets comprising the microgranules described above.

The subject of the invention is also the method for making themicrogranules described above according to which:

-   -   in a first step, a granulation solution comprising at least one        binder in a solvent is sprayed onto the individualized particles        of active principle maintained in suspension in a fluidized bed        until a core is obtained;    -   and then, in a second step, the core formed is coated by        spraying a coating suspension or solution based on particles of        active principle and binder, the coated core obtained then        having a substantially spherical shape.

In an advantageous embodiment, a step for drying the cores obtained isintercalated between the first and the second step.

According to another characteristic, the method may be performedcontinuously or batchwise.

Of course, the solvent in which the binder is dissolved will bedetermined as a function of the actual nature of the binder and will bechosen from aqueous or organic solvents, alone or in combination.

To solve the problem posed of obtaining coated cores whose size is assmall as possible, in any case below 500 micrometers, preferably below350 micrometers, the size of the particles of active principle used inthe first step is between 10 and 30 micrometers, advantageously 25micrometers, while the size of the particles of active principle used inthe second step is between 10 and 20 micrometers, advantageously below15 micrometers.

Of course, such sizes of particles of active principle may be obtainedby any methods known to persons skilled in the art, in particularmicronization or grinding.

In an advantageous embodiment, the size of the particles of activeprinciple used in the first step is identical to the size of those usedin the second step.

To check, during the method of manufacture, the size of themicrogranules as a function of the titer of active principle, the activeprinciple/binder ratio is constant during the first and second steps,advantageously equal to 90/10. Consequently, the second step may bestopped as soon as the desired size of the microgranule, below 500 μm,has been reached.

According to another characteristic, in a third step, at least oneadditional coating solution is sprayed, whose composition is chosen as afunction of the characteristics of masking of taste and/or of release ofactive principle desired.

As already stated, the method of the invention is formed in a fluidizedbed, advantageously by a bottom spray technique. The parameters of thefluidized bed (pressure, spraying rate, and the like) do not exhibitparticular characteristics and will be adjusted in the customary mannerby persons skilled in the art.

The invention and the advantages resulting therefrom will emerge moreclearly from the following exemplary embodiments given by way ofillustration and without limitation.

EXAMPLE 1 Manufacture of Microgranules of Ibuprofen

a) Composition of the Coated Core

ibuprofen 1600 g HPMC 606*  160 g *manufactured by SHIN-ETSUb) Preparation of the Granulating Solutions and Coating Suspension

Granulating Solution

40 g of HPMC 606 are introduced into 360 g of purified water, withstirring until complete dissolution of the hydroxymethyl propylcellulose is obtained.

Coating Suspension

1 200 g of micronized ibuprofen (25μ) and 120 g of HPMC 606 in 3 080 gof purified water are mixed together, with constant stirring untilcomplete dissolution of the hydroxypropyl methyl cellulose is obtained.

c) Manufacture of the Coated Core

400 g of ibuprofen having a particle size equal to 25 micrometers areintroduced into a fluidized bed apparatus of the GLATT GPCG 1 typeequipped with a Bottom Spray tank, while the active principle is kept ata temperature sufficient to avoid sticking together while the mass iskept moist.

The granulating solution prepared above is then sprayed until a corehaving a median particle size of about 100 micrometers is obtained.

After drying the core thus formed, the active principle-based coatingsuspension is continuously sprayed until a granule is obtained which hasa median particle size of between 250 and 300 micrometers.

d) Functional Coating

A polymeric dispersion of ethyl cellulose and HPMC and syloid is appliedto the coated core in order to mask the taste of the active principle.

EXAMPLE 2 Manufacture of Microgranules of Tinidazole

a) Composition of the Coated Core

tinidazole 1600 g Eudragit ® E 100  160 gb) Manufacture of the Coated Core

Example 1 is repeated, replacing HPMC with Eudragit® E 100 and purifiedwater with ethanol.

The Eudragit® is chosen as binder, but also for its function as agentmasking the taste of the active principle, while allowing its immediaterelease. This thereby makes it possible to improve the masking of thetaste from the granulation step, before the optional functional coatingstep.

EXAMPLE 3 Manufacture of Microgranules of Doxycyclin

a) Composition of the Coated Core

doxycyclin  15 kg PVP K90 1.5 kgb) Preparation of the Granulating Solutions and Coating Suspension

Granulating Solution

Preparation of a granulating solution of PVP K90 at 5% (w/w) in ethanol.

Coating Suspension

25 kg of the solution of PVP K90 at 5% in ethanol obtained above arecollected and 10 kg of doxycyclin (10μ) in 23.75 kg of ethanol are addedthereto.

c) Manufacture of the Coated Core

5 kg of doxycyclin (10μ) are introduced into a fluidized bed apparatusof the GLATT GPCG5 type equipped with a bottom spray tank and a 12″nozzle.

The granulating solution obtained above is then sprayed. After dryingthe core thus formed, the active principle-based coating suspension issprayed continuously until a granule having a median particle size ofabout 257 μm is obtained.

d) Functional Coating

A polymeric solution of Eudragit® E100 (manufactured by Röhm) at 12.5%(w/w) in ethanol is sprayed on the coated cores. The equivalent of 10%(w/w calculated as dry polymer) of the mass of the coated cores isapplied for masking taste.

The invention and the advantages resulting therefrom are clearly evidentfrom the description.

The possibility of making coated microgranules whose coated core has avery small size, below 300 micrometers, facilitating the functionalcoating and subsequent forming, will be noted in particular.

Although this invention has been described with reference to anillustrative embodiment, this description is not intended to limit thescope of the invention. Various modifications and combinations of theillustrative embodiments as well as other embodiments of the inventionwill be apparent to persons skilled in the art upon reference to thedescription. It is therefore intended that the appended claimsaccomplish any such modifications or embodiments.

1. A microgranule comprising: a core coated with at least one coatinglayer, wherein said core and said at least one coating layer eachcomprise between 80 and 95% by weight of active principle, and between 5and 20% by weight of at least one binder, wherein the activeprinciple/binder ratio is constant and equal to 90/10, and wherein themicrogranule has a substantially spherical shape and a size comprisingbetween 200 and 300 μm.
 2. The microgranule as claimed in claim 1,characterized in that the balance for 100% by weight of the core and ofthe coating layer consists exclusively of binder.
 3. The microgranule asclaimed in claim 1, characterized in that the binder contained in thecore and the binder contained in said coating layer are identical. 4.The microgranule as claimed in claim 1, characterized in that the bindercontained in the core and the binder contained in said coating layer aredifferent.
 5. The microgranule as claimed in claim 1, characterized inthat the binder is chosen from the group comprising ethyl cellulose,hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC),hydroxypropyl methyl cellulose (HPMC), acrylic polymers, methacrylicpolymers, ammonio-methacrylate copolymer, polyacrylate, methacrylic acidcopolymer and polyvinylpyrrolidone.
 6. The microgranule as claimed inclaim 1, characterized in that the size of the particles of activeprinciple varies between 10 and 30 μm.
 7. The microgranule as claimed inclaim 1, characterized in that the coated core comprises an additionalfunctional layer whose composition is chosen according to thecharacteristics of masking of taste and/or of release of activeprinciple desired.